A Peak Into Lipid Metabolism: The Lean Mass Hyper Responder Phenotype

A Peak Into Lipid Metabolism: The Lean Mass Hyper Responder Phenotype

The Emergence of the Lean Mass Hyper Responder (LMHR) Phenotype

With the rising popularity of carbohydrate restricted diets (CRDs), a new phenomena has emerged, being that of the lean mass Hyper Responder phenotype. This phenotype was named LMHR by Dave Feldman, a senior software engineer, entrepreneur, and citizen scientist. After Dave started a low carbohydrate diet, he found that his cholesterol numbers increased substantially. For instance, he arranged an experiment where he dropped his LDL-C by 73mg/dL and LDL-P by 1115 nm/L in just three days. With his expertise in engineering, Dave began to reverse engineer the lipid system through self-experimentation and testing, and ultimately discovered that in his case, it was quite dynamic. He found that his cholesterol would move up and down significantly in just  a matter of days.

What Is A LMHR?

The term "lean mass hyper-responder" (LMHR) refers to a specific phenotype observed in some individuals who adhere to a low-carbohydrate, high-fat diet, such as the ketogenic diet. This phenotype is characterized by significant changes in lipid profiles, especially marked by:

  • Elevated LDL-C: Individuals with the LMHR phenotype experience unusually high levels of low-density lipoprotein cholesterol (LDL-C). This is notable because LDL-C is typically considered "bad" cholesterol, associated with an increased risk of cardiovascular disease.
  • High HDL-C: HDL cholesterol (HDL-C), often referred to as "good" cholesterol, is usually higher in LMHRs. Elevated HDL-C levels are generally considered protective against heart disease.
  • Low Triglycerides: Despite high total and LDL cholesterol levels, LMHRs typically have low triglyceride levels, which is another factor that's generally considered favorable in cardiovascular risk assessments.
  • The term "lean mass" in LMHR refers to individuals who have a relatively low body fat percentage and a higher proportion of lean muscle mass. People with the LMHR phenotype are often physically active and lean, which contributes to the distinctiveness of their lipid profiles compared to the general population or individuals with different metabolic states.
  • Specific requirements: LDL-C ≥ 200, HDL-C ≥ 80, and TG ≤ 70 mg/d.

The Lean Mass Hyper Responder Case Study

In 2017, co-author of the study “Case Report: Hypercholesterolemia “Lean Mass Hyper Responder” Phenotype Presents in the Context of a Low Saturated Fat Carbohydrate-Restricted Diet,” Dave Feldman, overserved a trend in which individuals who were lean as well as athletic tended to observe larger increases in LDL-C on carb restricted diets (CRDs). He also found that while LDL-C was increasing, HDL-C also increased, while triglycerides (TG) decreased. While elevated LDL-C can be a concern when it comes to the development of atherogenic dyslipidemia, the combination of increased HDL-C and decreased TG make this opposite to that of atherogenic dyslipidemia.

Dave Feldman proposed the LMHR phenotype in 2017, and since then, more and more people have reported meeting the requirements of the LMHR phenotype, likely due to the increased trend of individuals using CRDs. With the requirements of this phenotype defined, an experiment took place to explore this newly discovered phenomena.

Case Description And Findings

In this study, an individual, LM, is a 26-year-old male with a medical history of ulcerative colitis, diagnosed at the age of 21. LM was being treated with oral and suppository mesalamine and hydrocortisone enemas and was unable to sustain remission for longer than 8 weeks. Then, at the age of 23, LM adopted a Mediterranean-style ketogenic diet, and since adopting this, LM has only experienced colitis flares on three occasions. These flares occurred twice when trying to reintroduce honey, fruit, and/or starchy vegetables, and once following acute mold exposure.

While adhering to the ketogenic diet (KD), LM’s LDL-C increased from 95 mg/dl (considered to be healthy) to 321 mg/dl (considered to be quite high), with low TGs and an increased HDL from 48 to 109 mg/dl. An important thing to note here is that LM prioritized foods rich in unsaturated fat, and restricted foods higher in saturated fat such as red meat and dairy, while consuming around 30g of fiber per day, and then dropping to 15g of fiber per day.

LM’s cholesterol over the course of two years (from August 2020 to October 2021) were considered to be quite high, ranging from 392 mg/dl and 545 mg/dl throughout. His final lipid panel during that two-year period was 411 mg/dl, and his doctors recommended that he go on a statin drug to manage his high LDL-C with the presumed goal being to prevent atherosclerotic buildup. LM however, considered a compromise with his doctor. He agreed to undergo pharmacotherapy (in this case statin therapy), if it was first proven that he was developing atherosclerotic plaque. So, a coronary computer tomography angiography (CCTA) was order for calcified and non-calcified plaques, and no plaque or stenosis was observed in any vessels CAD-RADS =0.

 

Image from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9048595/

Two additional key figures in this study are Nick Norwitz, PhD, and Adrian Soto-Mota, PhD. They play significant roles in the research and collaborate closely with Dave Feldman to further investigate the subject. Nick Norwitz has notably applied a Mediterranean-style ketogenic diet to successfully manage his ulcerative colitis and discovered that he also falls into the lean mass hyper-responder (LMHR) category. He is recognized for his unique self-experiment titled “Oreo Cookie Treatment Lowers LDL Cholesterol More Than High-Intensity Statin Therapy in a Lean Mass Hyper-Responder on a Ketogenic Diet: A Curious Crossover Experiment,” which will be discussed in a separate post.

What Is The Significance Here?

While this phenomenon is still undergoing investigation, this experiment shows that our understanding of lipid metabolism needs to be explored further. While elevated LDL-C in individuals may be a cause for concern, in individuals that adhere to CRD and/or are LMHRs, it may not be.

With my primary area of study being in nutrition, something does come to mind, although once again, this information is new, so I will not be making any claims here. In individuals that are fat adapted, meaning their primary source of energy production comes from fats (lipids), perhaps this elevated LDL-C is due to increased energy needs via fat when carbohydrates are not present. This is idea can be further explained by the emerging idea of the lipid energy model (LEM).

The Lipid Energy Model

While undergoing carbohydrate restriction, peripheral tissues are in greater demand for fat-based fuel such as ketone bodies, non-esterified fatty acids (NEFAs) and TG-rich lipoproteins. The lipid energy model proposes that in metabolically healthy individuals, there is an increase in very low density lipoproteins (VLDL) secretion, LPL-mediated TG hydrolysis and VLDL turnover, which results in lipid profiles that correspond to the LMHR phenotype.

So, in lean individuals, limiting carbohydrate intake leads to a greater reliance on fat for energy. This shift prompts the liver to release more triglycerides (TG) carried in very low-density lipoproteins (VLDL), which are then broken down by lipoprotein lipase, leading to significant increases in both LDL-C and HDL-C levels, while keeping TG levels low.

 

Image from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9048595/

In conclusion, the lean mass hyper-responder (LMHR) phenotype represents a significant shift in our understanding of lipid metabolism in the context of carbohydrate-restricted diets (CRDs). Initiated by Dave Feldman's observations and self-experiments, this phenomenon highlights the dynamic nature of cholesterol levels in individuals consuming low-carbohydrate, high-fat diets. The case studies, including LM's experience with ulcerative colitis and dietary changes, along with contributions from researchers like Nick Norwitz and Adrian Soto-Mota, further illustrate the complexities and individual variations in lipid responses to diet. The emergence of the LMHR phenotype and the lipid energy model challenges traditional views on cholesterol and heart health, especially in the context of CRDs and metabolic health. As this area of research expands, it may lead to a deeper understanding of the relationship between diet, lipid metabolism, and overall health, suggesting that the traditional one-size-fits-all approach to dietary guidelines and cholesterol management may need reevaluation in light of individual metabolic responses.

If you would like to dive further into this, you should check out Nick Norwitz and Dave Feldman’s social media pages which are provided below. These two are on the cutting edge of lipid energy metabolism and are a breath of fresh air in the space of nutritional sciences.

Nick Norwitz:

Dave Feldman:

References and links of note:

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